GPR120: A bi-potential mediator to modulate the osteogenic and adipogenic differentiation of BMMSCs.
GPR120: A bi-potential mediator to modulate the osteogenic and adipogenic differentiation of BMMSCs.
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GPR120：一种调节 BMMSC 成骨和脂肪分化的双电位介质。
DOI：
10.1038/srep14080
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发表时间：
2015-09-14
影响因子：
4.6
通讯作者：
Luo ZJ
中科院分区：
文献类型：
--
作者：
Gao B;Huang Q;Jie Q;Lu WG;Wang L;Li XJ;Sun Z;Hu YQ;Chen L;Liu BH;Liu J;Yang L;Luo ZJ
游离脂肪酸除了参与细胞新陈代谢外，还通过GPCRs表现出不同的信号分子效应。GPR120是一种G蛋白偶联的长链不饱和脂肪酸受体，已被报道在脂质代谢中介导脂肪形成。然而，GPR120是否也介导成骨和调控BMMSCs仍不清楚。在这项研究中，我们发现GPR120以配体剂量依赖的方式靶向BMMSCs的双潜能分化。高浓度的TUG-891(一种高度选择性的GPR120激动剂)通过Ras-ERK1/2级联途径促进成骨，而低浓度的TUG-891则通过Ras-ERK1/2级联途径促进P38和脂肪的生成。GPR12 0的精细分子调控是通过上调不同的整合素亚基(α1、α2和β1；α5和β3)实现的。大剂量的TUG-891在体内挽救了雌激素缺乏的骨丢失，进一步支持了GPR120在骨代谢中的重要作用。我们的发现首次表明，GPR120介导的细胞信号以剂量依赖的方式决定了BMMSCs的双潜能分化。此外，不同整合素亚基的诱导参与了ERK和p38磷酸化之间的拉锯式平衡的细胞质调节。这些发现为通过调节GPR120介导的BMMSCs分化平衡来治疗骨质疏松症提供了新的希望。
Free fatty acids display diverse effects as signalling molecules through GPCRs in addition to their involvement in cellular metabolism. GPR120, a G protein-coupled receptor for long-chain unsaturated fatty acids, has been reported to mediate adipogenesis in lipid metabolism. However, whether GPR120 also mediates osteogenesis and regulates BMMSCs remain unclear. In this study, we showed that GPR120 targeted the bi-potential differentiation of BMMSCs in a ligand dose-dependent manner. High concentrations of TUG-891 (a highly selective agonist of GPR120) promoted osteogenesis via the Ras-ERK1/2 cascade, while low concentrations elevated P38 and increased adipogenesis. The fine molecular regulation of GPR120 was implemented by up-regulating different integrin subunits (α1, α2 and β1; α5 and β3). The administration of high doses of TUG-891 rescued oestrogen-deficient bone loss in vivo, further supporting an essential role of GPR120 in bone metabolism. Our findings, for the first time, showed that GPR120-mediated cellular signalling determines the bi-potential differentiation of BMMSCs in a dose-dependent manner. Additionally, the induction of different integrin subunits was involved in the cytoplasmic regulation of a seesaw-like balance between ERK and p38 phosphorylation. These findings provide new hope for developing novel remedies to treat osteoporosis by adjusting the GPR120-mediated differentiation balance of BMMSCs.